NOD1 and NOD2 signalling links ER stress with inflammation.
NOD1 and NOD2 signalling links ER stress with inflammation.
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DOI：
10.1038/nature17631
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发表时间：
2016-04-21
期刊：
影响因子：
64.8
通讯作者：
Tsolis RM
中科院分区：
文献类型：
--
作者：
Keestra-Gounder AM;Byndloss MX;Seyffert N;Young BM;Chávez-Arroyo A;Tsai AY;Cevallos SA;Winter MG;Pham OH;Tiffany CR;de Jong MF;Kerrinnes T;Ravindran R;Luciw PA;McSorley SJ;Bäumler AJ;Tsolis RM
内质网（ER）应激是炎症性疾病，如克罗恩病和2型糖尿病的主要贡献者。ER应激诱导未折叠蛋白反应（UPR），这涉及三种跨膜受体的激活，即ATF6（转录激活因子6）、PERK（蛋白激酶RNA样内质网激酶）和IRE1 α（肌醇需要酶1 α）（扩展数据图1a）。一旦被激活，IRE 1 α将TRAF 2（TNF受体相关因子2）募集到ER膜，通过核因子κ B（NF-κ B）途径启动炎症反应。炎症通常在模式识别受体（PRR）（例如Toll样受体（TLR）或核苷酸结合寡聚化结构域（NOD）样受体（NLR））检测到组织损伤或微生物感染时触发。然而，目前尚不清楚哪些PRR在ER应激期间诱导炎症中起主要作用。在这里，我们表明，NOD1和NOD2，PRRs的NLR家族的两个成员，是ER应激诱导的炎症的重要介质。ER应激诱导剂毒胡萝卜素和二硫苏糖醇（DTT）以NOD 1/2依赖性方式触发促炎细胞因子白细胞介素（IL）-6的产生。由流产布鲁氏菌感染引发的炎症和IL-6产生是TRAF2、NOD 1/2和RIP2依赖性的，通过将IV型分泌系统（T4SS）效应蛋白VceC注射到宿主细胞中诱导ER应激，并且可以通过ER应激抑制剂牛磺熊去氧胆酸盐（TUDCA）或IRE1 α激酶抑制剂治疗来减弱。NOD1和NOD2与由IRE1 α/TRAF2信号通路诱导的促炎反应的关联提供了先天免疫和ER应激诱导的炎症之间的新联系。
Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn’s disease and type 2 diabetes. ER stress induces the unfolded protein response (UPR), which involves activation of three transmembrane receptors, ATF6 (activating transcription factor 6), PERK (protein kinase RNA-like endoplasmic reticulum kinase) and IRE1α (inositol-requiring enzyme 1α) (Extended Data figure 1a). Once activated, IRE1α recruits TRAF2 (TNF receptor-associated factor 2) to the ER membrane to initiate inflammatory responses via the nuclear factor kappa B (NF-κB) pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) or nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), detect tissue damage or microbial infection. However, it is not clear which PRRs play a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NLR family of PRRs, are important mediators of ER stress-induced inflammation. The ER stress inducers thapsigargin and dithiothreitol (DTT) triggered production of the pro-inflammatory cytokine interleukin (IL)-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system (T4SS) effector protein VceC into host cells, was TRAF2, NOD1/2 and RIP2-dependent and could be blunted by treatment with the ER-stress inhibitor tauroursodeoxycholate (TUDCA) or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signaling pathway provides a novel link between innate immunity and ER stress-induced inflammation.